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Enhanced inflammatory potential of CD4+ T-cells that lack proteasome immunosubunit expression, in a T-cell transfer-based colitis model.
- Source :
-
PloS one [PLoS One] 2014 Apr 16; Vol. 9 (4), pp. e95378. Date of Electronic Publication: 2014 Apr 16 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Proteasomes play a fundamental role in intracellular protein degradation and therewith regulate a variety of cellular processes. Exposure of cells to (pro)inflammatory cytokines upregulates the expression of three inducible catalytic proteasome subunits, the immunosubunits, which incorporate into newly assembled proteasome complexes and alter the catalytic activity of the cellular proteasome population. Single gene-deficient mice lacking one of the three immunosubunits are resistant to dextran sulfate sodium (DSS)-induced colitis development and, likewise, inhibition of one single immunosubunit protects mice against the development of DSS-induced colitis. The observed diminished disease susceptibility has been attributed to altered cytokine production and CD4+ T-cell differentiation in the absence of immunosubunits. To further test whether the catalytic activity conferred by immunosubunits plays an essential role in CD4+ T-cell function and to distinguish between the role of immunosubunits in effector T-cells versus inflamed tissue, we used a T-cell transfer-induced colitis model. Naïve wt or immunosubunit-deficient CD4+ T-cells were adoptively transferred into RAG1-/- and immunosubunit-deficient RAG1-/- mice and colitis development was determined six weeks later. While immunosubunit expression in recipient mice had no effect on colitis development, transferred immunosubunit-deficient T- cells were more potent in inducing colitis and produced more proinflammatory IL17 than wt T-cells. Taken together, our data show that modifications in proteasome-mediated proteolysis in T-cells, conferred by lack of immunosubunit incorporation, do not attenuate but enhance CD4+ T-cell-induced inflammation.
- Subjects :
- Adoptive Transfer
Animals
CD4-Positive T-Lymphocytes pathology
CD4-Positive T-Lymphocytes transplantation
Colitis chemically induced
Colitis genetics
Colitis pathology
Dextran Sulfate
Disease Models, Animal
Female
Gene Deletion
Homeodomain Proteins genetics
Homeodomain Proteins immunology
Inflammation chemically induced
Inflammation genetics
Inflammation immunology
Inflammation pathology
Interleukin-17 biosynthesis
Interleukin-17 immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteasome Endopeptidase Complex genetics
Protein Subunits genetics
CD4-Positive T-Lymphocytes immunology
Colitis immunology
Gene Expression immunology
Proteasome Endopeptidase Complex immunology
Protein Subunits immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24740379
- Full Text :
- https://doi.org/10.1371/journal.pone.0095378